Long-term Treatment for Cancer Patients With Deep Venous Thrombosis or Pulmonary Embolism

NCT01164046 | Terminated Phase 3 DMC

• 2 other identifiers: EudraCT nr: 2009-015336-15Protocol nr: 29462
• Study Type: interventional
• Target: 56
• Locations: 5 countries
• Sites: 14

Brief Summary

Background Patients with cancer and a first deep venous thrombosis of the leg or pulmonary embolism (venous thromboembolism, VTE) are generally treated with low molecular weight heparin (LMWH)injections for 6 months, since this treatment is associated with a reduced incidence of recurrent VTE compared to vitamin K antagonists (VKA). It is recommended that patients with active malignancy (metastatic cancer and/or ongoing cancer treatment)continue anticoagulant treatment. However, it is unknown whether LMWH is still superior compared to VKA for the long-term anticoagulant treatment. Aim The aim of this study is to evaluate whether low-molecular-weight heparin more effectively reduces recurrent VTE compared to vitamin K antagonists in patients with cancer who have already completed 6 to 12 months of anticoagulant treatment because of deep venous thrombosis of the leg or pulmonary embolism. Hypothesis The investigators hypothesize that LMWH is more effective compared to VKA in the long-term treatment of VTE in cancer patients who have already been treated for 6-12 months with anticoagulants. Design This is a multicenter, multinational, randomized, open label trial. Patients Patients with a malignancy (all types, solid and hematological) who have received 6-12 months of anticoagulation for VTE and have an indication for continuing anticoagulation, will be randomly assigned to six additional months of LMWH or VKA. LMWH will be administered in a weight-adjusted scheme, with 65-75% of therapeutic doses. All types of LMWH and VKA are allowed, as long as weight adjusted dosing is possible for LMWH. The target INR will be 2.0-3.0. The primary efficacy outcome is symptomatic recurrent VTE, i.e. deep vein thrombosis and pulmonary embolism. The primary safety outcome is major bleeding. Sample size A total of 65 to 87 recurrent VTE events are needed to show a 50% reduction with LMWH as compared to VKA (type I error 0.05, two-sided, power respectively 80 and 90%). To observe 75 events, with a 10% event rate per half year in the VKA arm and 5% in the LMWH arm a total of 1000 patients will need to be included. Organisation Outcomes will be adjudicated by a central adjudication committee. A steering committee will be formed, preferably consisting of one member of every participating center. An electronic case report form will be used for data collection. Also, an electronic trial master file will be used.

Conditions

Venous Thromboembolism; Neoplasms

Keywords

anticoagulants; Heparin, Low-Molecular-Weight; 4-Hydroxycoumarins; recurrent venous thrombosis

Outcome Measures

Primary Outcomes (1)

• Symptomatic recurrent VTE, i.e. the composite of recurrent deep venous thrombosis and fatal or non-fatal pulmonary embolism

  Primary efficacy outcome

  6 months

Secondary Outcomes (2)

• All clinically relevant bleeding (i.e. major bleeding and other clinically relevant non-major bleeding)

  6 months

• all-cause mortality

  6 months

Study Arms (2)

vitamin K antagonists

ACTIVE COMPARATOR

Drug: vitamin K antagonists

Low molecular weight heparin

ACTIVE COMPARATOR

Drug: low molecular weight heparin

Interventions

low molecular weight heparin DRUG

weight adjusted dose of low molecular weight heparin, any type allowed if approved, 65-75% of full therapeutic dose

Also known as: nadroparin, enoxaparin, tinzaparin, bemiparin, reviparin, dalteparin, certoparin

Low molecular weight heparin

vitamin K antagonists DRUG

Target INR between 2-3. Any type allowed, if approved for use in that country.

Also known as: phenprocoumon, acenocoumarol, warfarin

vitamin K antagonists

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with cancer and confirmed pulmonary embolism (PE) or deep vein thrombosis (DVT) of the leg who have been treated for minimally 6 and maximally 12 months with therapeutic doses of anticoagulants, i.e. LMWH or VKA or a new anticoagulant in a trial
• Written informed consent
• Indication for long-term anticoagulant therapy (e.g. because of metastasized disease, chemotherapy)

You may not qualify if:

• Legal age limitations (country specific), minimum age at least 18 years
• Indications for anticoagulant therapy other than DVT or PE
• Any contraindication listed in the local labeling of LMWH or VKA
• Childbearing potential without proper contraceptive measures, pregnancy or breastfeeding
• Life expectancy \<3 months

Sponsors & Collaborators

• University Medical Center Groningen: lead

Study Sites (14)

George Washington University

Washington D.C., District of Columbia, 20037, United States

Location

University Health Network

Toronto, Ontario, Canada

Location

Medical Clinic Dresden University

Dresden, Germany

Location

Ospedali Riuniti

Bergamo, Italy

Location

Hospital d'Annunziata

Chieti, Italy

Location

Ospedaliera di Padova

Padua, Italy

Location

Arcispedale Santa Maria Nuova (ASMN)

Reggio Emilia, Italy

Location

Ospedale di Circolo

Varese, Italy

Location

Flevoziekenhuis

Almere Stad, Netherlands

Location

Academic Medical Centre (AMC)

Amsterdam, Netherlands

Location

Slotervaart Hospital

Amsterdam, Netherlands

Location

Reinier de Graaf Groep

Delft, Netherlands

Location

Medisch Spectrum Twente

Enschede, Netherlands

Location

University Medical Centre Groningen (UMCG)

Groningen, Netherlands

Location

Related Publications (4)

• Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. doi: 10.1056/NEJMoa025313.

  PMID: 12853587 BACKGROUND

• Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002 Aug 12-26;162(15):1729-35. doi: 10.1001/archinte.162.15.1729.

  PMID: 12153376 BACKGROUND

• Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C, Jahanzeb M, Kakkar A, Kuderer NM, Levine MN, Liebman H, Mendelson D, Raskob G, Somerfield MR, Thodiyil P, Trent D, Francis CW; American Society of Clinical Oncology. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007 Dec 1;25(34):5490-505. doi: 10.1200/JCO.2007.14.1283. Epub 2007 Oct 29.

  PMID: 17968019 BACKGROUND

• Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):381S-453S. doi: 10.1378/chest.08-0656.

  PMID: 18574271 BACKGROUND

MeSH Terms

Conditions

Venous Thromboembolism; Neoplasms; Venous Thrombosis

Interventions

Heparin, Low-Molecular-Weight; Nadroparin; Enoxaparin; Tinzaparin; bemiparin; reviparin; Dalteparin; certoparin; acarboxyprothrombin; Phenprocoumon; Acenocoumarol; Warfarin

Condition Hierarchy (Ancestors)

Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Thrombosis

Intervention Hierarchy (Ancestors)

Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Pieter W. Kamphuisen, MD, PhD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

• Harry R. Buller, MD, PhD

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  PRINCIPAL INVESTIGATOR

• Steering Board Committee

  Representatives from participating centers

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof

Study Record Dates

• First Submitted: July 15, 2010
• First Posted: July 16, 2010
• Study Start: August 1, 2010
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2014
• Last Updated: December 3, 2014

Record last verified: 2014-12

Locations

DE (1); US (1); IT (5); NL (6); CA (1)